This proposal seeks to develop a novel vaccine against Lyme disease -- by targeting Ixodes scapularis proteins critical for Borrelia burgdorferi transmission from the tick to mammalian host. Earlier work has identified four tick proteins, Salp15, TRE31, tHRF and TSLPI, that facilitate different steps of spirochete transmission and immunity against these proteins individually provided partial impairment of spirochete transmission to the murine host. Simultaneously targeting these proteins might compromise multiple steps of transmission and effectively thwart transmission. Towards this new strategy to prevent Lyme disease, we will assess the efficacy of vaccine targeting: A. A combination of Borrelia-interacting tick proteins, TRE31, and Salp15, to impair interactions that facilitate spirochete egress from the gut and interactions that ensure spirochete survival in the host respectively; B. A combination of Borrelia-assisting salivary proteins, Tick Salivary Lectin Pathway Inhibitor (TSLPI) and tick histamine release factor (tHRF), that do not physically associate with the spirochete, but play a significant role in enhancing spirochete survival in the host during transmission and in tick engorgement respectively; and C. A combination of Borrelia-interacting (Salp15 and TRE31) and Borrelia-assisting (TSLPI and tHRF) tick proteins to effectively thwart spirochete arrival and survival at the tick bite-site. Such a systematic approach has hitherto not been explored and could in principle also be applicable to thwart other arthropod- borne pathogens. The success of this multipronged derailment approach will provide the basis for the formulation of a multivalent tick antigenic peptide-based vaccine against Lyme disease in Phase II efforts.